Intrapericardial botulinum toxin treatment for bradycardia

ABSTRACT

Methods for treating cardiac muscle disorders, such as cardiac arrhythmias, by administration of a neurotoxin to cardiac muscle are disclosed. Bradycardia can be alleviated for several months by a single intrapericardial or intracardiac injection or infusion of a botulinum toxin. Tachycardia can be alleviated by preganglionic sympathetic nervous system administration of a botulinum toxin.

BACKGROUND

The present invention relates to a method for treating cardiac muscledisorders. In particular, the present invention relates to a method fortreating cardiac arrhythmia by administration of a neurotoxin to cardiacmuscle.

The pumping action of the heart is controlled by sympathetic andparasympathetic (primarily vagal) nerves which abundantly innervate theheart. Heart rate can be increased by sympathetic stimulation anddecreased by vagal stimulation. Additionally, many cardiac fibers, suchas the sinus node (also called sinoatrial or SA node) have thecapability of self-excitation. Stimulation of the sympathetic nervescauses release of norepinephine at the sympathetic nerve endings.Contrarily, stimulation of the parasympathetic nerves to the heartcauses acetylcholine to be released at the vagal nerve endings. Hence,the parasympathetic nervous system is often referred to as a cholinergicsystem.

The release of acetylcholine by the postganglionic parasympathetic nerveendings, by acting upon the muscarinic receptors present in cardiacmuscle tissue, as indicated, decreases the rate of rhythm of the sinusnode and decreases the excitability of the AV junctional fibers betweenthe atrial musculature and the AV node, thereby slowing transmission ofthe cardiac impulse into the ventricles. The major site of action ofparasympathetic control of the heart appears to be the sinoatrial node,where it reduces the heart rate in contrast to sympathetic stimulation.Other lesser parasympathetic activities include inhibition of the AVnode and a mild inhibitory effect on contractile force.

In athletes, parasympathetic activity can increase to slow the heartrate. With excessive physical training, the AV node can be inhibited toblock the conduction of the impulse from the SA node to the ventricles,resulting in the condition referred to as AV block.

Notably, all preganglionic neurons are cholinergic in both thesympathetic and parasympathetic nervous systems. Therefore acetylcholineor acetylcholine like substances when applied to the ganglia will exciteboth sympathetic and parasympathetic postganglionic neurons.Additionally, all or almost all of the postganglionic neurons of theparasympathetic nervous system are also cholinergic. Acetylcholineactivates two types of receptors, muscarinic and nicotinic receptors.Parasympathomimetic drugs such as pilocarpine and methacholine mimic theeffect of acetylcholine.

Arrhythmia

Cardiac muscle disorders, such as arrhythmias and fibrillations, canresult in incapacitation and death. During ventricular fibrillation, theventricles can quiver in an irregular chaotic way so that little bloodis pumped out of the heart and the body, particularly the brain, isdeprived of oxygen. During ventricular tachycardia, the heart beats toofast because of rapid electrical impulses starting in the ventricles,which also decreases bloodflow and deprives the body of oxygen.

Natural cardiac rhythms are maintained through the cooperation ofsympathetic nerves, which can increase the rate at which the heartbeats, and the vagus nerve which can slow down the rate at which theheart beats.

Electrochemical messages from the sympathetic and vagal nerves reach theheart's natural pacemaker, the sinoatrial node, progress to the upperchambers (the atria), and pause at the atrioventricle node, beforeentering the main pumping chambers, the ventricles. Any breach of thiselectricalchemical circuit can cause the heart to lurch into a chaoticrhythm.

Arrhythmias are caused by a disruption of the normal functioning of theelectrical conduction system of the heart. Normally, the chambers of theheart (atria and ventricles) contract in a coordinated manner. Thesignal to contract is an electrical impulse that begins in thesinoatrial node (sinus or SA node). This impulse is conducted throughthe atria and stimulates them to contract. The impulse passes throughthe atrioventricular node, then travels through the ventricles andstimulates them to contract. Problems can occur anywhere along theconduction system, causing various arrhythmias. Problems can also occurin the heart muscle itself, causing it to respond differently to thesignal to contract, also causing arrhythmias, or causing the ventriclesto contract independently of the normal conduction system.

Arrhythmias include tachycardias, bradycardias and true arrhythmias ofdisturbed rhythm. Arrhythmias are classified as lethal if they cause asevere decrease in the pumping function of the heart. When the pumpingfunction is severely decreased for more than a few seconds, bloodcirculation is essentially stopped, and organ damage (such as braindamage) can occur within a few minutes. Lethal arrhythmias includeventricular fibrillation, also ventricular tachycardia that is rapid andsustained, or pulseless, and may include sustained episodes of otherarrhythmias. Additional types of arrhythmias include atrial fibrillationor flutter, multifocal atrial tachycardia, paroxysmal supraventriculartachycardia, Wolff-Parkinson-White syndrome, sinus tachycardia, sinusbradycardia, bradycardia associated with heart block, sick sinussyndrome, and ectopic heartbeat.

In sinus arrhythmia there are cyclic changes in the heart rate duringbreathing. In sinus tachycardia the sinus node sends out electricalsignals faster than usual, speeding up the heart rate. In sick sinussyndrome the sinus node does not fire its signals properly, so that theheart rate slows down. Sometimes the rate changes back and forth betweena slow (bradycardia) and fast (tachycardia) rate. With prematuresupraventricular contractions or premature atrial contractions (PAC) aheart beat occurs early in the atria, causing the heart to beat beforethe next regular heartbeat. In supraventricular tachycardia (SVT) andparoxysmal atrial tachycardia (PAT) a series of early beats in the atriaspeed up the heart rate (the number of times a heart beats per minute).In paroxysmal tachycardia repeated periods of very fast heartbeats beginand end suddenly. In atrial flutter there are rapidly fired signalswhich cause the heart muscles in the atria to contract quickly, leadingto a very fast, steady heartbeat. In atrial fibrillation electricalsignals in the atria are fired in a very fast and uncontrolled manner.The electrical signals arrive in the ventricles in a completelyirregular fashion, so the heart beat is completely irregular. In theWolff-Parkinson-White syndrome, abnormal pathways between the atria andventricles cause the electrical signal to arrive at the ventricles toosoon and to be transmitted back into the atria. Thus very fast heartrates may develop as the electrical signal ricochets between the atriaand ventricles.

Arrhythmias which originate in the ventricles include prematureventricular complexes (PVC) in which an electrical signal from theventricles causes an early heart beat that generally goes unnoticed. Theheart then seems to pause until the next beat of the ventricle occurs ina regular fashion. In ventricular tachycardia the heart beats fast dueto electrical signals arising from the ventricles (rather than fromtheatria). In ventricular fibrillation electrical signals in theventricles are fired in a very fast and uncontrolled manner, causing theheart to quiver rather than beat and pump blood.

It is known that some arrhythmias are also caused by some drugs. Theseinclude antiarrhythmics, Beta blockers, caffeine, cocaine,psychotropics, and sympathomimetics.

Tests that reveal arrhythmias, and which can differentiate between thedifferent types of arrhythmia, include echocardiogram (ECG or EKG),coronary angiography and electrophysiologic study (EPS), the laterrequiring cardiac catheterization. An ECG records the changingpotentials of the electrical field imparted by the heart.Echocardiography refers to a group of tests that utilize ultrasound toexamine the heart and record information in the form of reflected sonicwaves. Magnetic resonance imaging can also be used as a noninvasivemeans to determine, at least to some extent, intracardiac pressures andcardiac anatomy. Further details regarding theses diagnostic procedurescan be found in Heart Disease A Textbook of Cardiovascular Medicine,edited by Eugene Braunwald, (1997), two volumes, fifth edition,published by W.B. Saunders Company, the entire contents of which isincorporated herein by reference in its entirety.

Therapy for arrhythmia can include systemic administration (by oral orintravenous routes) of an antiarrhythmic drug, surgical removal of thearrhythmic tissue, and/or or implantation of a defibrillator orpacemaker.

Drug Therapy for Arrhythmia

The traditional treatment for the erratic heartbeat of arrhythmia isoral or intravenous administration of an antiarrhythmic drug. A widevariety of antiarrhythmic drugs, such as amiodarone and sotalol, areknown, as set forth in Drugs for the Heart by Lionel H. Opie (1997)published by W. B. Saunders Company, the entire contents of which areincorporated herein by reference in its entirety. Antiarrhythmic drugsare generally classified based on their major effects on the heart.Category IA drugs include quinidine, procainamide and disopyramide.Category IB drugs include lidocaine, mexiletine. Category IC drugsinclude flecainide and propafenone. Category II drugs include beta-blocking drugs. Category III drugs include amiodarone, ibutilide andsotalol. Category IV drugs include calcium-blocking drugs. The categoryIA, IC and III antiarrhythmic drugs have the major side effects oftorsades de points and sudden death. See e.g. Chapter 7. “AntiarrhythmicDrugs” in Drugs for the Heart, supra and Nattel, S., ComparativeMechanisms of Action of Antiarrhythmic Drugs, Am J. Cardiol, 72: 13F–17F(1993), and Wit, A., Electrophysiological Basis for Antiarrhythmic DrugAction, Clin. Physiol. Biochem. 3: 127–134 (1985), both of which latertwo publications are incorporated herein in their entireties.

Certain arrhythmias, such as atrial fibrillation, can occurpost-operatively and various drugs have been administered bothpre-operatively and re-initiated immediately after surgery as anintravenous medication to try and treat this condition. Unfortunately,drugs such as sotalol administered intravenously to treat post-operativeatrial fibrillation can cause ventricular pro-arrhythmia. Additionally,conditions such as obstructive lung disease and congestive heart failurelimit the use of beta blockers antiarrhythmic drugs such as sotalol.

A significant problem with the use of most if not all antiarrhythmicdrugs occurs because antiarrhythmic drugs are typically administeredintravenously or intraperitoneally resulting in rapid metabolicclearance rates, with concomitant short duration of effective drug leveland low drug efficiency. Furthermore, a number of the antiarrhythmicdrugs can also have proarrhythmic effects upon the heart.

Thus, current drug therapy for arrhythmia whether by oral or parenteraladministration into the systemic circulation has many drawbacks anddeficiencies, including undesired and deleterious systemic side effects(lack of selectivity), short duration of action and substantialantigenicity (drug resistance). Additionally, the antiarrhythmic drugsused are expensive, require the person being treated to remember to takethem on at least a daily basis, can render the patient groggy andlethargic and are contraindicated for certain patients.

Bradycardia

Significantly, almost one half of all unexpected cardiac arrests whichresult in sudden death are caused by bradyarrhythmia. Bradyarrhythmia orsynonymously bradycardia can be defined as any disturbance of theheart's rhythm which results in a heart rate of under sixty beats perminute. Bradyarrhythmia may occur without obvious underlying cause andwithout the existence of a previous event such as a myocardialinfarction or pulmonary embolism.

Tragically, it is known that sudden death in heart failure resultingfrom acute myocardial ischemia or infarction, pulmonary embolism,embolic or hemorrhagic stroke, hyperalemia as well as conduction systemdisease can all be caused by a prior bradycardiac episode.

Drugs that block the effect of acetylcholine, and hence the inhibitoryeffect of the vagal nerve on the heart, upon the muscarinic type ofcholinergic effector organs include atropine and similar drugs such ashomatropine and scopolamine. These drugs do not affect the nicotinicreceptor action of acetylcholine on the postganglionic neurons or onskeletal muscle. Atropine has a vagolytic effect that is useful for themanagement of bradyarrhythmias with atrioventricular (AV) block,particularly with inferior infarction, sinus or nodal bradycardia withhypotension, or bradycardia-related ventricular ectopy. Small doses andcareful monitoring are essential since the elimination of vagalinhibition may unmask latent sympathetic overactivity, thereby producingtachycardia.

Unfortunately, while symptomatic sinus bradycardia, sick sinus syndromeand sinoatrial disease can be treated with probanthine or by chronicadministration of atropine, the results are unsatisfactory in the longrun so that implantation of a cardiac pacemaker is the typicaltherapeutic choice for chronic bradycardia. Additionally, for AV blockwith syncope or with excessively slow heart rates, atropine orisoproterenol or transthoracic pacing has been used as an emergencymeasure, but again, only pending pacemaker implantation. Thus, manydrawbacks and deficiencies exist with current therapy for bradycardia.

Surgical Removal of Arrhythmic Tissue

Surgery can be carried out to excise the cardiac tissue causing anarrhythmia where the arrhythmia is unresponsive to antiarrhythmic drugtherapy. Although closed approaches, such as by biotome catheterizationhave been used for some of cardiac surgery such as for example, toremove myxomas, including atrial myxomas, closed approach surgicaltreatment of arrhythmic cardiac tissue is typically treated by eithercatheter mediated cryoablation or by radiofrequency ablation.Radiofrequency ablation has been used to treat tachycardias such assupraventricular tachycardias and some ventricular tachycardias.

In radiofrequency ablation a catheter enclosing conductive wires withterminal electrodes near the open end or tip of the catheter is insertedinto a patient's body through a vein in the thigh, shoulder, or neck.Upon being threaded intravenously to the heart, the catheter tip ispositioned inside the heart next to the abnormal heart tissue that isresponsible for the tachycardia. Then, a small amount (about 50 watts)of energy is applied to the heart between the tip electrode and a skinpatch that is usually placed behind the left shoulder. This energy heatsup and thus dries out the heart tissue that is within about 5millimeters of the tip. After about 30 to 60 seconds of heating, thistissue is no longer alive and can no longer cause tachycardia. Althoughthe actual ablation takes only a minute, the procedure often takes 4 to10 hours. The reason being that it is time-consuming to identify theexact tissue in the heart that is responsible for a tachycardia and tomake sure that all of the relevant tissue has been ablated completely.

Cardiac arrhythmias treatable by radiofrequency ablation includeatrioventricular nodal reentrant tachycardia (AVNRT), atrioventriculartachycardia (AVRT) that uses an accessory bypass tract for retrogradeconduction, atrial tachycardias that occur in otherwise-normal heartsand also in hearts that have had prior surgery, atrial flutter, and somekinds of ventricular tachycardia that occur in otherwise-normal hearts.The first three rhythms are often grouped together with the term“supraventricular tachycardia”, although this term can also be used toinclude atrial flutter and atrial fibrillation.

Subsequent to radiofrequency, a cardioverter-defibrillator is oftenimplanted in the patient to prevent recurrence of subsequent arrhythmiaby non-ablated cardiac tissues.

Unfortunately, while radiofrequency ablation can treat, it usually doesnot cure supraventricular tachycardias, including atrial flutter andatrial fibrillation. When a tachycardia is not controlled byantiarrhythmic drugs and cannot be cured by ablation, the symptoms ofthe arrhythmia (but not the arrhythmia itself can often be controlled byeither intentional destruction of the AV node itself or by ablation ofthe slow AV nodal pathway. In intentional destruction of the AV node, byAV junctional ablation, the upper and lower chambers of the heart areelectrically disconnected and the procedure mandates immediateimplantation of a permanent pacemaker. AV nodal ablation is used tocontrol otherwise unresponsive atrial fibrillation.

Ablation of the slow AV nodal pathway is the same procedure used totreat AV nodal reentrant tachycardia. For uncontrollable atrialfibrillation and other supraventricular tachycardias, this procedureoffers some of the benefit of AV junctional ablation without the needfor implantation of a permanent pacemaker. The slow AV nodal pathwayprocedure takes advantage of the fact that the heart in most patientshas two parts to the AV node. The “fast” AV nodal pathway conductsrapidly but takes a long time to recover enough to conduct the nextheart beat. The “slow” AV nodal pathway is a backup pathway thatconducts slowly but can recover very quickly. At most heart rates,patients use only the fast pathway. When the heart is beating veryrapidly (during vigorous exercise, for example), the slow pathway isused because the fast pathway can't recover fast enough between heartbeats. When the slow pathway is removed by ablation, the patient almostnever can tell the difference at usual heart rates (even during vigorousexercise to, say, a heart rate of 180-200 beats per minute). If a veryrapid heart rate (say, to 250 bpm) occurs in the atria, however, theventricles will go more slowly than they would with an intact slowpathway.

In older patients, who are the ones who usually develop sustained atrialfibrillation, the fast pathway does not conduct as rapidly as in youngpeople, so the maximum heart rate can often be reduced to a range thatis tolerable. Two problems with the slow AV nodal procedure for atriafibrillation are, first, when the procedure is continued until the heartrate in atrial fibrillation is reasonable (say, 130 bpm during infusionof isoproterenol, which speeds up the heart rate), about 20% of patientsget complete heart block and require immediate implantation of apermanent pacemaker. Second, patients who have undergone the slow AVnodal procedure often don't feel as well as those who go ahead and haveAV junctional ablation and pacemaker insertion. The reason seems to bethat the heart rate is still erratic because the ventricular rhythmstill follows the irregularly atrial fibrillation. By contrast, patientswho have AV junctional ablation and pacemakers have regular rhythmsbecause the pacemakers set the heart rate for them.

Unfortunately, the radiation used during the ablation procedure canpotentially cause cancer, especially breast cancer in women.

Hyperlipidemia doesn't affect the supraventricular rhythms that are theusual targets of ablation. When ablation is used for the type ofventricular tachycardia that occurs in people who have had myocardialinfarction, however, control of hyperlipidemia is quite important toprevent recurrent infarction.

Finally, arrhythmia can also be treated by implantation of a cardiacdefibrillator or by implantation of an artificial pacemaker. A cardiacdefibrillator is surgically implanted beneath the skin of a patient'sabdomen and connected by wires to the ventricles. When arrhythmiaoccurs, the defibrillator sends an electrical charge to the heart in anattempt to restore normal heartbeat. A defibrillator does not preventthe onset of arrhythmia, but merely attempts to restore the heart'snormal rhythm by providing an electric shock to the heart to disrupt anongoing arrhythmia. Importantly, both defibrillators and pacemakers canmalfunction and misfire due, for example to the effect of proximity toan airport metal detector or store security check out device.Furthermore, significant drawback to the use of both defibrillators andpacemakers include the requirement for surgery to implant with attendantrisks such as infection.

Angina

A commonly prescribed drug for angina is nitroglycerin, which relievespain by widening blood vessels. More blood can thereby flow to the heartmuscle and the work load of the heart is decreased. Nitroglycerin can beadministered when discomfort occurs or is expected. Other drugs to treatangina include beta blockers to slow the heart rate and lessen the forceof the heart muscle contraction and calcium channel blockers forreducing the frequency and severity of angina attacks.

Botulinum Toxin

The anaerobic, gram positive bacterium Clostridium botulinum produces apotent neurotoxin, botulinum toxin, which causes a neuroparalyticillness in humans and animals referred to as botulism. The spores ofClostridium botulinum can grow in improperly sterilized and sealed foodcontainers of home based canneries, which are the cause of many of thecases of botulism. The effects of botulism typically appear 18 to 36hours after eating the foodstuffs infected with a Clostridium botulinumculture. The botulinum toxin passes unattenuated through the lining ofthe gut and attacks the central nervous system. Symptoms of botulinumintoxication progress from difficulty walking, swallowing, and speakingto paralysis of the respiratory muscles, resulting in suffocation anddeath.

Botulinum toxin is the most lethal natural biological agent known toman. It has been determined that 39 units per kilogram of intramuscularBOTOX® is a LD₅₀ in primates. One unit (U) of botulinum toxin can bedefined as the LD₅₀ upon intraperitoneal injection into mice. BOTOX®contains 4.8 ng of botulinum toxin type A per 100 unit vial. Thus, for a70 kg human a LD₅₀ of 39 U/kg would be about 131 ng or 27.3 vials (2730units) of intramuscular BOTOX®. Seven immunologically distinct botulinumtoxins have been characterized, being respectively botulinum toxinserotypes A, B, C1, D, E, F and G each of which is distinguished byneutralization with type-specific antibodies. The neurotoxin componentis noncovalently bound to nontoxic proteins to form high molecularweight toxin complexes. The different serotypes of botulinum toxin varyin the animal species that they affect and in the severity and durationof the paralysis they evoke. Botulinum toxin type A is the most potentof the seven known serotypes produced by the Clostridium botulinumbacteria and has, in minute quantities, become an importantpharmaceutical for the treatment of various segmental and peripheralmovement disorders associated with muscle overactivity, such asspasticity, as well as pain, and various other neuronal disorders.

At a normal neuromuscular junction, a nerve impulse triggers the releaseof acetylcholine, which causes the muscle to contract. Hyperactivemuscle contraction is characterized by excessive release ofacetylcholine at the neuromuscular junction. The use of a botulinumtoxin can be effective in reducing the excessive activity by blockingthe release of acetylcholine at the neuromuscular junction.

Botulinum toxin is known to act to reduce excess muscle (both skeletaland smooth muscle) and sphincter contraction and to reduce certainglandular activities upon direct injection into the hyperactive orhypertonic muscle or gland and is believed to exert its effect byentering peripheral nerve terminals at the neuromuscular junction and byblocking the release of acetylcholine. Affected terminals are inhibitedfrom stimulating muscle contraction or inducing glandular activity,resulting in a reduction of muscle tone or reduce secretory output bythe targeted gland. Thus, when injected intramuscularly at therapeuticdoses, botulinum toxin produces a localized chemical denervation andhence a localized weakening or paralysis and relief from excessiveinvoluntary muscle contractions. When the muscle is chemicallydenervated, it atrophies and may then in response developextrajunctional acetylcholine receptors.

Clinical effects of peripheral intramuscular botulinum toxin are usuallyseen within one week of injection. The typical duration of symptomaticrelief from a single intramuscular injection average about three monthsor longer. Muscles therapeutically treated with a botulinum toxineventually recover from the temporary paralysis induced by the toxin,due possibly to the development of new nerve sprouts or to reoccurrenceof neurotransmission form the original synapse, or both. A nerve sproutestablishes a new neuromuscular junction. Thus, neuromusculartransmission can gradually return to normal over a period of severalmonths with no lasting side effects.

Botulinum toxin has no appreciable affinity for organs or tissues otherthan cholinergic neurons and when it does bind to neuronal receptors,its only known action is to block acetylcholine release without causingneuronal cell death. Botulinum toxin has therefore been used to treat avariety of disorders of cholinergic nervous system transmission.

Botulinum toxins have been used for the treatment of an increasing arrayof neurologic disorders, most of which are characterized by hyperactiveneuromuscular activity in specific focal or segmental muscle regions.Thus intramuscular or intraglandular injection of one or more of thebotulinum toxin serotypes has been used to treat, blepharospasm,spasmodic torticollis, hemifacial spasm, spasmodic dysphonia, oralmandibular dystonia and limb dystonias, myofacial pain, headache,bruxism, achalasia, trembling chin, spasticity, juvenile cerebral palsy,hyperhydrosis, excess salivation, non-dystonic tremors, cosmetictreatment of brow furrows, focal dystonias, spasticity, tensionheadache, migraine headache and lower back pain. Not infrequently, asignificant amount of pain relief has also been experienced. Thesebenefits have been observed after local intramuscular injection of, mostcommonly botulinum toxin type A, or one or another of the otherbotulinum neurotoxin serotypes.

The following list sets forth total (not per kg of patient weight) unitsof administrations of BOTOX® that have been used for therapeuticintramuscular injections. The list therefore provides guidelines for theunit amount of BOTOX® that can be used to denervate other, not listed,cholinergic muscles or muscle elements of similar size, such as cardiacmuscle tissues and cardiac muscles elements. Thus, it is known that:

-   -   (1) about 75–125 units of BOTOX® per intramuscular injection        (multiple muscles) can be used to effectively treat cervical        dystonia;    -   (2) 5–10 units of BOTOX® per intramuscular injection can be used        to effectively treat glabellar lines (brow furrows) (5 units        injected intramuscularly into the procerus muscle and 10 units        injected intramuscularly into each corrugator supercilii        muscle);    -   (3) about 30–80 units of BOTOX® can be used to effectively treat        constipation by intrasphincter injection of the puborectalis        muscle;    -   (4) about 1–5 units per muscle of intramuscularly injected        BOTOX® can be used to effectively treat blepharospasm by        injecting the lateral pre-tarsal orbicularis oculi muscle of the        upper lid and the lateral pre-tarsal orbicularis oculi of the        lower lid.    -   (5) to treat strabismus, each extraocular muscle to be treated        can be injected intramuscularly with between about 1–5 units of        BOTOX®, the amount injected varying based upon both the size of        the muscle to be injected and the extent of muscle paralysis        desired (i.e. amount of diopter correction desired). A maximum        dose per intramuscular injection should not exceed 25 U.    -   (6) to treat upper limb spasticity following stroke by        intramuscular injections of BOTOX® into five different upper        limb flexor muscles, as follows:        -   (a) flexor digitorum profundus: 7.5 U to 30 U        -   (b) flexor digitorum sublimus: 7.5 U to 30 U        -   (c) flexor carpi ulnaris: 10 U to 40 U        -   (d) flexor carpi radialis: 15 U to 60 U        -   (e) biceps brachii: 50 U to 200 U. Each of the five            indicated muscles can be injected at the same treatment            session, so that the patient receives from 90 U to 360 U of            upper limb flexor muscle BOTOX® by intramuscular injection            at each treatment session.

Botulinum serotypes B, C1, E and F demonstrate a lower potency thanBOTOX® and would therefore be used in greater amounts.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures.Botulinum toxin type A is available from several commercial sources,including Allergan, Inc., of Irvine, Calif. under the tradename BOTOX®Botulinum Toxin Type A purified complex and from Porton Products, Ltd.,U.K. under the trade name DYSPORT.

Dickson, in J. Exper Med 37, 711–311 (1923) disclosed that the initialvagal nerves stimulation required to induce the physiological responseof fewer heart beats per unit time was about eight times higher inbotulinum intoxicated cats than it was in non-botulinum intoxicatedcats.

All the botulinum serotypes are initially synthesized as inactive singlechain proteins which must be cleaved or nicked by proteases to becomeneuroactive. The bacterial strains that make serotypes A and G possessendogenous proteases and these serotypes are therefore recovered frombacterial cultures predominantly in their active from. In contrast,types C1, D and E are synthesized by nonproteolytic strains and aretherefore unactivated when recovered from culture. Serotypes B and F areproduced by both proteolytic and nonproteolytic strains and may berecovered in either the active or inactive form. However, even theproteolytic strains that produce the type B serotype only cleave aportion of the toxin produced. The exact proportion of nicked tounnicked molecules depends on the length of incubation and thetemperature of the culture. Therefore, a certain percentage of anypreparation of type B toxin is likely to be inactive. The presence ofinactive botulinum toxin molecules in a clinical preparation willcontribute to the overall protein load of the preparation, which hasbeen linked to increased antigenicity, without contributing to itsclinical efficacy.

Although all botulinum toxins serotypes inhibit acetylcholine release atthe neuromuscular junction, they do so by affecting differentneurosecretory proteins and/or cleaving these proteins at differentsites. For example, botulinum types A and E both cleave the 25kiloDalton (kD) synaptosomal associated protein (SNAP-25), but theytarget different amino acid sequences within this protein. Botulinumtoxin types B, D, F and G act on vesicle-associated protein (VAMP, alsocalled synaptobrevin), with each serotype cleaving the protein at adifferent site. Finally, botulinum toxin type C1 has been shown tocleave both syntaxin and SNAP-25. These differences in mechanism ofaction may affect the relative potency and/or duration of action of thevarious botulinum toxin serotypes.

The size of an active botulinum toxin protein is determined by both thesize of the neurotoxin-molecule (150 kD for all serotypes) and itsassociated non-toxin proteins, which vary widely between serotypes. TypeA is produced in both a 900 kD and a 500 kD form. Types B and C1 as a500 kD complex only. Type D as both a 300 kD and 500 kD form. And typesE and F as approximately 300 kD complexes only. Larger complexes containhemaglutinin and a non-toxic nonhemaglutinin protein that improve thestability of the toxin molecule for oral absorption. It is possible thatthe larger complexes may have a slower rate of diffusion away from asite of injection.

Acetylcholine

Almost invariably, only a single type of small molecule neurotransmitteris released by each type of neuron in the mammalian nervous system. Theneurotransmitter acetylcholine is secreted by neurons in many areas ofthe brain, but specifically by the large pyramidal cells of the motorcortex, by several different neurons in the basal ganglia, by the motorneurons that innervate the skeletal muscles, by the preganglionicneurons of the autonomic nervous system (both sympathetic andparasympathetic), by the postganglionic neurons of the parasympatheticnervous system, and by some of the postganglionic neurons of thesympathetic nervous system. Essentially, only the postganglionicsympathetic nerve fibers to the sweat glands, the piloerector musclesand a few blood vessels are cholinergic and most of the postganglionicneurons of the sympathetic nervous system secret the neurotransmitternorepinephine. In most instances acetylcholine has an excitatory effect.However, acetylcholine is known to have inhibitory effects at some ofthe peripheral parasympathetic nerve endings, such as inhibition of theheart by the vagus nerves.

The efferent signals of the autonomic nervous system are transmitted tothe body through either the sympathetic nervous system or theparasympathetic nervous system. The heart receives many sympatheticnerve fibers from the neck portion of the sympathetic chain. Thepreganglionic neurons of the sympathetic nervous system extend frompreganglionic sympathetic neuron cell bodies located in theintermediolateral horn of the spinal cord. The preganglionic sympatheticnerve fibers, extending from the cell body, synapse with postganglionicneurons located in either a paravertebral sympathetic ganglion or in aprevertebral ganglion. Since, the preganglionic neurons of both thesympathetic and parasympathetic nervous system are cholinergic,application of acetylcholine to the ganglia will excite both sympatheticand parasympathetic postganglionic neurons.

Specific application of acetylcholine to the preganglionic sympatheticneurons which innervate the heart can result in tachycardia, as well asan increased force of contraction of the heart. Contrarily, specificapplication of acetylcholine to the preganglionic parasympatheticneurons which innervate the heart can result in bradycardia (as well asa decreased force of contraction of the heart, especially of the atria),the same bradycardiac result being obtained by application ofacetylcholine to the postganglionic parasympathetic neurons which resideon or within cardiac muscle.

Acetylcholine activates two types of receptors, muscarinic and nicotinicreceptors. The muscarinic receptors are found in all effector cellsstimulated by the postganglionic neurons of the parasympathetic nervoussystem, as well as in those stimulated by the postganglionic cholinergicneurons of the sympathetic nervous system. The nicotinic receptors arefound in the synapses between the preganglionic and postganglionicneurons of both the sympathetic and parasympathetic. The nicotinicreceptors are also present in many membranes of skeletal muscle fibersat the neuromuscular junction.

What is needed therefore is a method for treating cardiac arrhythmiasuch as bradycardia and tachycardia without the numerous drawbacks anddeficiencies of: (1) antiarrhythmic drug treatments, such as systemiceffects, lack of specificity, and short duration of activity; (2)surgical, cryo or radiofrequency ablation, and; (3) which has alongevity of efficacy which can remove or significantly reduce the needfor implantation of a pacemaker in order to substantially restore theheart's natural rhythm.

SUMMARY

The present invention meets this need and provides antiarrhythmic drugtreatment methods for treating bradycardia and tachycardia withoutsystemic effects, with specificity of drug action, with a relativelylong duration of drug activity, without a need to carry out surgical,cryo or radiofrequency ablation, and with the longevity of drug efficacyby the disclosed methods permitting removal or significant reduction inthe need for implantation of a pacemaker in order to substantiallyrestore the heart's natural rhythm. Furthermore, methods within thescope of the present invention dramatically reduce the previouslyrequired daily antiarrhythmic drug administration frequency.

A preferred method within the scope of the present invention fortreating a cardiac muscle disorder can be carried out by administering aneurotoxin to a patient suffering from a present or prospective cardiacmuscle disorder. The cardiac muscle disorder can be a bradycardia or atachycardia. In the case of a bradycardia, the administration step canbe carried out by administration of the neurotoxin to or to the vicinityof a postganglionic parasympathetic neuron or by administration of theneurotoxin to or to the vicinity of a preganglionic parasympatheticneuron. In the case of a tachycardia, the administration step can becarried out by administration of the neurotoxin to or to the vicinity ofa preganglionic sympathetic neuron.

Another preferred method within the scope of the present invention canbe carried out by locally administering the neurotoxin to a cardiacmuscle to treat the cardiac muscle disorder. Local administration of theneurotoxin to the desired cardiac muscle can be carried out byintrapericardial injection or infusion of the neurotoxin, by therapeuticcardiac catheterization or by direct intracardiac muscle injection ofthe neurotoxin.

Cardiac catheterization can be carried out by inserting a catheter whichcomprises a first end and a second end, and a hollow needle attached tothe first end of the catheter into the circulatory system of a patient.Next the catheter is threaded within the circulatory system to the siteof the cardiac muscle disorder. At this point, the hollow needle isinserted into the site of the cardiac muscle disorder. This is followedby injection of the selected neurotoxin into the cardiac muscle.Finally, the catheter is removed from the patient's circulatory system.

It is believed that the neurotoxin acts by inhibiting formation orrelease of a neurotransmitter, such as acetylcholine, from neurons inthe vicinity of the cardiac muscle to be treated. Preferably, theneurotoxin is a botulinum toxin, such as botulinum toxin A which islocally administered to the cardiac muscle in an amount between about0.01 U/kg and about 35 U/kg. More preferably, the botulinum toxin A islocally administered to the cardiac muscle in an amount of between about0.1 U/kg to about 30 U/kg. Most preferably, the botulinum toxin A islocally administered to the cardiac muscle in an amount of between about1 U/kg and about 25 U/kg.

A further preferred method within the scope of the present invention fortreating a cardiac arrhythmia, such as a bradycardia, can comprise thesteps of administration of a first antiarrhythmic drug, followed byadministration of botulinum toxin. The first antiarrhythmic drug can beadministered orally or parenterally. By parenteral administration it ismeant that the first antiarrhythmic drug is not administered by eitheroral, intrapericardial or intracardiac routes of administration. Byintracardiac administration it is meant, administration directly ontothe surface of or into cardiac tissue, such as can be accomplished by,for example, therapeutic cardiac catheterization and by direct injectioninto cardiac muscle. In this method, the botulinum toxin can beadministered intrapericardially or intracardially.

Preferably, the first antiarrhythmic drug is selected from the groupconsisting of atropine, amiodarone, sotalol, quinidine, procainamide,diiospyramide, lidocaine, mexiletine, flecainide, propafenone, betablocking drugs, amiodarone, ibutilide and calcium blocking drugs withatropine and its salts and derivatives being a preferred firstantiarrhythmic drug.

The botulinum toxin can be selected from the group consisting ofbotulinum serotypes, A, B, C1, D, E, F and G and preferably, thebotulinum toxin is botulinum toxin type A.

A final preferred method within the scope of the present invention fortreating a mammalian cardiac muscle disorder, such as bradycardia, canhave the step of locally administering a therapeutically effectiveamount of a neurotoxin, such as botulinum toxin type A, to a cardiacmuscle. Preferably, between about 10 U and about 300 U of the botulinumtoxin type A is administered by the local administration step. Morepreferably, between about 20 U and about 200 U of the botulinum toxintype A is administered by the local administration step.

The site of cardiac muscle local administration, for treatingbradycardia, is preferably the sinoatrial node and the localadministration of the botulinum toxin type A can be carried out byeither intrapericardial or by cardiac catheterization administrationroutes.

DESCRIPTION

The present invention is based upon the discovery that localadministration of a neurotoxin to cardiac muscle can significantlyalleviate cardiac muscle disorders, such as arrhythmia. Particulararrhythmias treatable by the present invention include bradycardia andtachycardia. By local administration it is meant that the neurotoxin isadministered directly to, in, or to the vicinity of, the cardiac muscleto be treated. Local administration includes intrapericardial,intracardiac cardiac catheterization and direct cardiac muscle injectionroutes of administration for the neurotoxin. Peripheral muscleintramuscular, intrasphincter (i.e. in the GI tract), intraglandular,oral, transdermal and subcutaneous drug administration routes areunsuited for the practice of the present invention and are excluded fromits scope.

I have discovered that a particular neurotoxin, botulinum toxin, can beused with dramatic ameliorative effect to treat both acute and chronicarrhythmia, significantly superceding thereby current antiarrhythmicdrug therapy and additionally substantially removing the need to implanta pacemaker in a previously arrhythmic patient.

Thus, when atropine is ineffective and the patient has symptomaticbradycardia, vagal nerve inhibition and hence an increase in heart ratecan be accomplished by administration of botulinum toxin to the heart,as for example in the vicinity of the SA node. Botulinum toxinadministration can be accomplished by direct local injection to cardiacmuscle, by cardiac catheterization or by intrapericardial injection orinfusion. Significantly, a single administration injection of thebotulinum toxin substantially reduces the symptoms of the bradycardiafor from about two to about four months.

Administration of botulinum toxin according to the methods of thepresent invention can be used to treat and thereby reduce the occurrenceof the symptoms of, inter alia, bradycardia induced acute myocardialischemia or infarction, pulmonary embolism, embolic or hemorrhagicstroke, hyperalemia and conduction system disease. The resultingreduction of the incidence of bradyarrhythmia results directly in adecrease in the occurrence of cardiac arrest and ensuing sudden death.

Additionally, I have discovered that a neurotoxin such as a botulinumtoxin can be used to treat bradycardia induced post surgical atrialfibrillation. Atrial fibrillation in the immediate post-operative periodfollowing cardiac surgery is a common clinical problem, occurring in10–40% of patients. As with atrial fibrillation in any clinical setting,post-operative atrial fibrillation is associated with rapid ventricularresponse, congestive heart failure, and arterial embolization andstroke. Independent of these complications, post-operative atrialfibrillation is also an important cause of increased hospital length ofstay and increased hospital costs in these patients.

The parasympathetic nerves (the vagi) are distributed mainly to thesinus (SA) and AV nodes, to a lesser extent to the muscle of the twoatria and even less to the ventricular muscle. Thus, for the treatmentof bradycardia a preferred site of administration of the botulinum toxinis by local administration to ventricular muscle due to the presence ofvagal nerves therein. A more preferred site of administration of thebotulinum toxin for the treatment of bradycardia is by localadministration to either or both of the muscles of the atria due to thegreater distribution of parasympathetic nerve endings therein. A mostpreferred site of administration of the botulinum toxin for thetreatment of bradycardia is by local administration to or to thevicinity of the SA and/or AV nodes because the most extensivedistribution of parasympathetic nerve endings in cardiac muscles is atthe indicated nodes.

When intrapericardial injection or infusion of a solution of botulinumtoxin to the desired cardiac muscle location is carried out, needleguidance can be assisted by cardiac fluoroscopy or by more sensitive andspecific imaging modalities such as magnetic resonance imaging andcomputed tomography.

The route of administration and amount of botulinum toxin administeredcan vary widely according to the particular cardiac muscle disorderbeing treated and various patient variables including size, weight, age,disease severity and responsiveness to therapy. Method for determiningthe appropriate route of administration and dosage are generallydetermined on a case by case basis by the attending physician. Suchdeterminations are routine to one of ordinary skill in the art (see forexample, Harrison's Principles of Internal Medicine (1997), edited byAnthony Fauci et al., 14 ^(th) edition, published by McGraw Hill). Forexample, to treat bradycardia a solution of botulinum toxin isadministered by intrapericardial injection to facilitate contact of thetoxin with postganglionic parasympathetic nerve ending, while avoidingentry into the systemic circulation.

The specific dosage appropriate for administration is readily determinedby one of ordinary skill in the art according to the factor discussedabove. Additionally, the estimates for appropriate dosages in humans canbe extrapolated from determinations of the amounts of botulinum requiredfor effective denervation of other non-cardiac muscles. Thus, the amountof botulinum A to be injected is proportional to the mass of the cardiacmuscle to be denervated. Generally, between about 0.01 and 30 units of abotulinum toxin per kg of total patient weight can be administered toeffectively accomplish a toxin induced reversible postganglionicvagectomy upon administration of the neurotoxin at or to the vicinity ofarrhythmic cardiac tissue. Less than about 0.01 U/kg of a botulinumtoxin does not have a significant therapeutic effect, while more thanabout 30 U/kg of a botulinum toxin approaches the safety margin for atoxic dose. In exigent circumstances, up to about 35 U/kg of a botulinumtoxin can be administered by local administration. Careful placement ofthe injection needle and a low volume of neurotoxin used preventssignificant amounts of botulinum toxin from appearing systemically. Amore preferred dose range is from about 0.1 U/kg to about 25 U/kg of abotulinum toxin. A most preferred dose range is from about 1 U/kg toabout 20 U/kg of BOTOX®. The actual amount of U/kg of a botulinum toxinto be administered depends upon factors such as the extent (mass) of thearrhythmic tissue to be treated and the administration route chosen(i.e. by cardiac catheterization or by intrapericardial administration).Botulinum toxin type A is a preferred botulinum toxin serotype for usein the methods of the present invention.

I have found that the pericardial space can be safely and rapidlyaccessed for use as a drug delivery reservoir to which can be delivereda therapeutic dose of botulinum toxin for treatment of an arrhythmicheart. Thus, local cardiac drug delivery without system drug effect canbe accomplished by accessing the normal pericardial space through theright atrial (transatrial therefore) appendage. Pericardialadministration is a preferred method for administering botulinum toxinto the heart according to the present invention. For example, safe andrapid percutaneous subxyphoid access to the normal pericardium can beachieved using known methodologies. Additionally, also within the scopeof the present invention is an iontophoretic transmyocardial method (asset forth in Circulation 85; 4; 1582–1593 (1992), the contents of whichpublication are incorporated herein in its entirety) adapted for localadministration of a neurotoxin to cardiac muscle.

Another preferred method for local administration of botulinum toxin tothe heart is by cardiac catheterization using a needle tip, infusionsleeve catheter, such as a drug delivery PTCA catheter. Alternatively,local intracardiac delivery of botulinum can be accomplished by use of amicroporous balloon catheter or by use of a local adhesive(intracardiac) delivery technique.

Local, intracardiac catheter mediated delivery of a neurotoxin can beaccomplished by use of a microporous infusion catheter (see e.g. AmHeart J. 1996 November; 132(5):969–72 and Cath & Cardiovasc Diagn 1997November;42(3):313–20) suitably modified to infuse the neurotoxindirectly into the adjacent cardiac tissue at a relatively high pressurewith minimal injury to the cardiac tissue. Other mechanisms for localintracardiac neurotoxin delivery include eluting stents, microspheres,neurotoxin-coated hydrogel (which can absorb hydrophilic drugs, such asbotulinum toxin) balloon, iontophoretic devices and endocardiac pavingand adhesive devices. The later method is carried out by catheterassisted lodging of a neurotoxin containing adhesive at or near a siteof arrhythmic cardiac tissue (see e.g. Int J Artificial Organs 1997June; 20(6):319–26).

Furthermore, the present invention also includes within its scope localadministration of a neurotoxin to cardiac muscle by controlled releaseimplants which are placed in direct contact with the pericardium, theepicardium or placed intracardially by catheterization. The neurotoxinis imbedded into or absorbed by the implant material prior to placementof the implant on or adjacent to a site of a cardiac muscle to betreated for a cardiac muscle disorder. Thus, the controlled releasematerials and procedure as set forth in J Cardio Pharm 24: 826–840(1994) (the contents of which publication are incorporated herein in itsentirety), can be adapted by one of ordinary skill in the art for localadministration of a neurotoxin according to the present invention.

The pericardium is composed of an outer fibrous layer and an innerserous membrane with a single layer of mesothelial cells. The innerserous layer is attached to the surface of the heart and epicardial fatto form the visceral pericardium and this inner serous layer reflectsback on itself to line the outer fibrous layer to form the parietalpericardium. Between these two layers lays the pericardial space, whichis the only potential space in the normal pericardium. Favorablepharmacokinetic profiles have been obtained for basic fibroblast growthfactor (bFGF) and nitroglycerin delivered into the pericardial space,using the pericardial space as a drug delivery reservoir for thedelivery of therapeutic agents to the heart. See e.g. Cath & CardiovascInterv 1999; May;47(1):109–11.

Pericardial access is routinely performed to drain pericardial effusionsas well as to administer drugs for the treatment of pericardial diseasessuch as malignant or infectious pericarditis. Access to the pericardialpace can be hindered by the difficulty of percutaneously entering thepericardial space in the absence of pericardial fluid. I have discoveredthat a therapeutically effective amount of an antiarrhythmic neurotoxincan be delivered to a normal (non fluid filled) percutaneously accessedpericardium. The method permits local intrapericardial delivery of atherapeutic dose of the neurotoxin delivery to arrhythmic cardiactissues.

Botulinum toxin can also be used as a prophylactic agent to treat post-operative atrial fibrillation. To treat post operative arrhythmia, thebotulinum toxin is locally administered 5–20 days before the surgery andagain after surgery. The benefits of prophylactic therapy can includesignificant reductions in morbidity, hospital length of stay and overallcosts. Botulinum toxin can also be used to treat angina.

EXAMPLES

The following examples provide those of ordinary skill in the art withspecific preferred methods within the scope of the present invention forcarrying out the present invention and are not intended to limit thescope of what the inventor regards as his invention.

For the practice of the methods set forth by Examples 1 and 2 below, thearrhythmic cardiac tissue to be injected with botulinum toxin ispinpointed by use of known electrophysiological means which, forexample, can be used to generate a computer simulation of each heartbeatas it moves across the heart. Tracking of heart beats in this mannerlocate areas of the heart capable of producing arrhythmias and therebyidentifies the sites or sites for therapeutic neurotoxin localadministration as set forth herein.

Example 1 Therapeutic Cardiac Catheterization To Treat Arrhythmia

Intracardiac arrhythmic tissues can be treated by a method of thepresent invention using a variety of cardiac catheterization procedures,as exemplified below.

(a) Direct, injection of botulinum toxin to cardiac muscle can becarried out by an endomyocardial procedure where the biotome is replacedby a hollow needle through which a bolus injection of the toxin can beaccomplished. Right ventricular injection can be accomplished byintroducing a No. 7-9F catheter with a retractable sheathed needle viathe right internal jugular vein using the usual Seldinger technique. Thecatheter is advanced under fluoroscopic guidance to the lateral wall ofthe right atrium. Using counterclockwise rotation, the catheter isadvanced across the tricuspid valve and toward the interventricularseptum. Position of the catheter against the interventricular septum isconfirmed using 30 degrees right anterior oblique and 60 degree leftanterior oblique fluoroscopic projections. Alternately, two dimensionalechocardiography can be used to guide the position of the catheter.Contact with the myocardium is confirmed by the presence of prematureventricular contractions, lack of further advancement and transmissionof ventricular impulse to the operator. The catheter sheath is thenwithdrawn to expose the needle tip. The catheter is readvanced tocontact the myocardium and embed the needle therein. Secure lodgment ofthe needle tip within the myocardial wall is confirmed by fluoroscopyand by resistance to an operator applied slight withdrawal pressure(tugging) upon the catheter. 0.3 U/kg to 5 U/kg of BOTOX® are theninjected into the myocardium and the catheter withdrawn. Right or leftventricular injection can also be accomplished from the femoral vein.The specific amount of BOTOX® administered by this intracardiacprocedure depends upon a variety of factors to be weighed and consideredwithin the discretion of the attending physician.

At the determined, localized site of arrhythmic cardiac tissue,botulinum toxin type A (available from Allergan, Inc., of Irvine, Calif.under the trade name BOTOX®) can be injected into the cardiac musclethrough a 4 mm sclerotherapy needle passed through the infusion channelof the catheter and connected to a gravity driven device (overhead) orpump for infusion of the BOTOX® into the selected cardiac tissue.

(b) An alternate cardiac catheterization can be used to locate arecessed needle tipped catheter at the site of arrhythmia generatingcardiac tissue. A thin flexible, hollow tube is inserted into thefemoral artery in the groin. The catheter is then advanced under x-rayguidance (fluoroscopy) through the aorta to the particular cardiactissue of interest. The purpose of cardiac catheterization is to injectthe neurotoxin into the previously determined cardiac muscle. Thepatient should not eat or drink anything after midnight the day prior tothe catheterization. A nurse will shave and wash the groin area to beinserted. The patient is hooked up to an EKG and a finger probe thatwill measure blood oxygen continuously.

A local anesthetic is applied to the groin area. The catheter isinserted and additional catheters can be inserted through the first one.The other catheters are pushed up though the aorta to the heart. Dye isinjected and x-rays taken to ensure proper placement of the catheters.

Subsequent to BOTOX®, neurotoxin efficacy can be evaluated by the samemeans used to evaluate the effect of anti-arrhythmic drugs, such as byelectrocardiogram (ECG).

Within seven days the bradycardia symptoms have substantially diminishedand remain significantly alleviated for two to four months postinjection. Insignificant amounts of the botulinum toxin appearsystemically with no significant side effects.

Example 2 Intrapericardial Injection to Treat Arrhythmia

(a) Intrapericardial injection of BOTOX® to treat an arrhythmia such asbradycardia is carried out by inserting a needle tip of a syringethrough the unopened chest wall, and guided by fluoroscopy, through thethin fibrous baglike structure of the pericardium which surrounds theheart and into a pericardial sinus, preferably without contacting theheart itself.

A bolus injection of the botulinum toxin can be released into a sinussuch as the transverse pericardial sinus adjacent to either the SA nodeor the AV node, at and in the vicinity of which the vagal nervesterminate on the heart. Preferably, the toxin is released at a locationwithin the pericardium, under the endocardium, intermediate between theSA and AV nodes so as to maximum immediate toxin contact with vagalnerve termini.

(b) An alternative intrapericardial procedure for local cardiac drugdelivery without system drug effect can also be accomplished byaccessing the normal pericardial space through the right atrialappendage. The transatrial technique for accessing the pericardial spaceis as follows. An 8-F multipurpose guide is positioned underfluoroscopic guidance in the right atrial appendage. A custom fabricated4-F catheter with a 21 gauge needle mounted at the tip is advancedthrough the guide, and a small perforation is made in the right atrialappendage. A soft 0.014 inch (0.036 cm) guide wire is advanced throughthe needle catheter and into the normal pericardial space. The guidewire confirms position in the pericardial space by conforming to thecontour of the heart, secures the point of entry and allows over thewire exchanges of other catheters. The needle catheter is withdrawn overthe wire and exchanged for a 4-F catheter with multiple side holes atits distal end, which is positioned and left in the pericardial spacefor delivery of neurotoxin. Radiopaque markers at the tip of allcatheters improves visualization during fluoroscopy. IntrapericardialBOTOX® 0.3 U/kg to U/kg is injected through the 4-F intrapericardialcatheter without rapid diffusion into the systemic circulation.

(c) A further alternative procedure by which the pericardial space canbe used as a drug delivery reservoir to deliver a therapeutic dose ofBOTOX® to the heart is by subxyphoid access. A 6 Fr arterial catheter isfemorally inserted for pressure monitoring. Safe and rapid percutaneoussubxyphoid access to the normal pericardium is accomplished by gentlyadvancing under fluoroscopic guidance an epidural introducer needle(Tuohy-17) with a continuous positive pressure of 20–30 mm Hg achievedby saline infusion using an intraflow system). The positive pressure isused to push the right ventricle (with a lower pressure) away from theneedle's path. Entry to the pericardial space is suspected after anincrease in the saline flow through the intraflow system. Access to thepericardial space is confirmed by the injection (intrapericardial) of 1ml of diluted contrast under fluoroscopy. A soft floppy-tip 0.025″guidewire is then advanced to the pericardial space and the needle isexchanged for an infusion catheter. Between about 0.3 U/kg and about 5U/kg of BOTOX® is injected.

(d) Alternatively, the arrhythmic tissue can be reached by endoscopythrough the chest wall and pericardium using a standard forward viewinginstrument or the site of the specific cardiac muscle area to beinjected can be localized using known cardiac imaging methods.

Whether the catheterization or intrapericardial local administrationroutes are selected for the BOTOX®, the present methods present highlyeffective methods for treating a cardiac muscle disorder, such asbradycardia, by local administration of a therapeutically effectiveamount of the BOTOX® to the cardiac muscle.

The disclosed method can locally administer between about 10 U and about300 U of the BOTOX® and preferably between about 20 U and about 200 U ofthe BOTOX® to or to the immediate vicinity of the cardiac muscle portionof the in vivo which generates or which assists in the generation of anacute or chronic episode of bradycardia. Thus, local administration ofthe BOTOX® to either or to both of the SA and AV nodes can be highlyeffective in the treatment of bradycardia. The specific unit amount ofBOTOX® to locally administer depends upon a number of factors, aspreviously specified, including the age and health of the patient, thesize of the patient's heart, the mass of arrhythmic cardiac tissue ofthe patient's heart to which the BOTOX® is to be locally administered,the local administration route and mechanism chosen, etc.

Example 3 Emergency Use of Botulinum Toxin

As a substitute or replacement for intravenous atropine, a patientexperiencing acute bradycardia and imminent demise can be treated byimmediate intraperitoneal injection of about 2 U/kg to about 35 U/kg ofBOTOX®, without pericardial imaging assist. The injection is carried outby inserting the syringe (between the ribs and into the chest wall for adistance depending on the amount of adipose tissue present and the sizeof the patient's chest cavity) until lodgment of the needle tip intocardiac muscle has been achieved, as evidenced by vibratory movement ofthe syringe. Bolus injection of the botulinum toxin is then carried out.The time to antiarrhythmic effect of the botulinum toxin depends upon anumber of factors, including the amount of BOTOX® locally administered.

A method for treating cardiac muscle disorders according to theinvention disclosed herein has many advantages, including the following:

-   -   1. systemic drug presentation with its attendant side effects        are avoided.

2. longevity of the effect of botulinum toxin obviates the need toimplant a defibrillator or pacemaker.

Although the present invention has been described in detail with regardto certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, a number of the botulinum toxin serotypes administered tothe postganglionic vagi nerve endings by various means can be used totreat a variety of cardiac muscle disorders. Additionally, otherbotulinum toxin serotypes, such as types B, C1, D, E, F and G can beused instead of and/or in conjunction with botulinum toxin type A.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

1. A method for treating bradycardia, the method comprising the step ofintrapericardial injection of a botulinum toxin to the sinoatrial nodeor to the atrioventricular node of a heart of a patient withbradycardia, thereby treating bradycardia.
 2. The method of claim 1,wherein the botulinum toxin is botulinum toxin type A and the amount ofbotulinum toxin type A locally administered to the heart is betweenabout 0.01 U/kg and about 35 U/kg.
 3. The method of claim 1 wherein thebotulinum toxin is botulinum toxin type A and the amount of botulinumtoxin type A locally administered to the heart is between about 0.1 U/kgand about 30 U/kg.
 4. The method of claim 1, wherein the botulinum toxinis botulinum toxin A and the amount of botulinum toxin A locallyadministered to the heart is between about 1 U/kg and about 25 U/kg. 5.The method of claim 1, wherein the botulinum toxin is selected from thegroup consisting of botulinum toxins types A, B, C, D, E, F and G.
 6. Amethod for treating bradycardia, the method comprising the step ofintrapericardial injection of botulinum toxin type A to the sinoatrialnode or to the atrioventricular node of a heart of a patient withbradycardia, thereby treating bradycardia.